Investigation of new 1,2,3-triazolyl-quinolinyl-propan-2-ol derivatives as potential antimicrobial agents: in vitro and in silico approach.

A new series of 1-((1-(4-substituted benzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(2-substituted quinolin-4-yl)propan-2-ol (9a-x) have been synthesized. The newly synthesized 1,2,3-triazolyl-quinolinyl-propan-2-ol (9a-x) derivatives were screened for in vitro antimicrobial activity against M. tuberculosis H37Rv, E. coli, P. mirabilis, B. subtilis, and S. albus. Most of the compounds showed good to moderate antibacterial activity and all derivatives have shown excellent to good antitubercular activity with MIC 0.8-12.5 µg/mL. To know the plausible mode of action for antibacterial activity the docking study against DNA gyrase from M. tuberculosis and S. aureus was investigated. The compounds have shown significant docking scores in the range of -9.532 to -7.087 and -9.543 to -6.621 Kcal/mol with the DNA gyrase enzyme of S. aureus (PDB ID: 2XCT) and M. tuberculosis (PDB ID: 5BS8), respectively. Against the S. aureus and M. tuberculosis H37Rv strains, the compound 9 l showed good activity with MIC values of 62.5 and 3.33 µM. It also showed significant docking scores in both targets with -8.291 and -8.885 Kcal/mol, respectively. Molecular dynamics was studied to investigate the structural and dynamics transitions at the atomistic level in S. aureus DNA gyrase (2XCT) and M. tuberculosis DNA gyrase (5BS8). The results revealed that the residues in the active binding pockets of the S. aureus and M. tuberculosis DNA gyrase proteins that interacted with compound 9 l remained relatively consistent throughout the MD simulations and thus, reflected the conformation stability of the respective complexes. Thus, the significant antimicrobial activity of derivatives 9a-x recommended that these compounds could assist in the development of lead compounds to treat for bacterial infections.Communicated by Ramaswamy H. Sarma.

Synthesis, Characterization, and Antimicrobial Activity Screening of Some Novel 3-(2-(3-(Substituted benzyloxy)oxetan-3-yl)-3-fluorophenoxy)-8-fluoro-2-methylquinoline Derivatives as Potential Antimycobacterial Agents.

Microbial infections remain a grave threat to global health security due to increasing antibiotic resistance. The coronavirus pandemic has increased the risk of microbial infection. To combat these infections, the search for new therapeutic agents is in high demand. A series of new 3-(2-(3-(substituted benzyloxy)oxetan-3-yl)-3-fluorophenoxy)-8-fluoro-2-methylquinoline (9a-i) derivatives have been synthesized. The structure of synthesized compounds was analyzed by spectroscopic methods. The newly synthesized oxetanyl-quinoline derivatives were evaluated for in vitro antibacterial activity against Escherichia coli (NCIM 2574), Proteus mirabilis (NCIM 2388), Bacillus subtilis (NCIM 2063), Staphylococcus albus (NCIM 2178), and in vitro antifungal activity against Aspergillus niger (ATCC 504) and Candida albicans (NCIM 3100). Six oxetanyl-quinoline derivatives 9a, 9b, 9c, 9d, 9e, and 9h have shown good antibacterial activity against P. mirabilis with MIC 31.25-62.5 µM, 3-(((3-(2-fluoro-6-((8-fluoro-2-methylquinolin-3-yl)oxy)phenyl)oxetan-3-yl)oxy)methyl)benzonitrile (9f) reporting comparable activity against P. mirabilis with respect to the standard drug streptomycin. Compound 9a also showed good activity against B. subtilis with MIC 31.25 µM. The eight compounds 9a, 9b, 9d, 9e, 9f, 9g, 9h, and 9i have shown good antifungal activity against A. niger. The synthesized compounds were also screened for antimycobacterial activity against Mycobacterium tuberculosis H37Rv by MTT assay. Among the nine derivatives, compounds 9b, 9c, 9d, 9f, 9g, 9h, and 9i showed excellent antimycobacterial activity with MIC 3.41-12.23 µM, and two derivatives showed good activity with MIC 27.29-57.73 µM. All the derivatives were further evaluated for cytotoxicity against the Vero cell line and were found to be nontoxic. The in silico study of compounds 9a-i was performed against ATP synthase (PDB ID: 4V1F) and most of the compounds showed the stable and significant binding to ATP synthase, confirming their plausible mode of action as ATP synthase inhibitors. Thus, the significant antimycobacterial activity of 3-(2-(3-(substituted benzyloxy)oxetan-3-yl)-3-fluorophenoxy)-8-fluoro-2-methylquinoline derivatives has suggested that the oxatenyl-quinoline compounds could assist in the development of lead compounds to treat mycobacterial infections.